Clefts of the lip and palate (CLP) comprise a large fraction of human birth defects, and are associated with a range of health complications. They require surgical, dental, speech, medical and behavioral interventions and impose a substantial economic and societal burden. CLP is the most prevalent birth defect in the United States, with about 6,800 new cases which includes cleft lip and/or palate, isolated and nonisolated born each year. There is a well documented, safe and inexpensive prevention for a related birth defect - those of the neural tube (NTD). Folic acid supplementation prior to pregnancy and during the first trimester shows that 4 mg per day will decrease NTD recurrence risks by about 70%. A few studies have also suggested decreased risks of recurrence of oral clefts with folic acid but these studies suffer from serious design limitations, and the real effect of folic acid on CLP recurrence remains to be demonstrated. It is critical to conduct a robust, large-scale, double-blinded, randomized clinical trial that clearly addresses this question. In this project we will complete the evaluation of the effect on prevention of CLP recurrence of periconceptual supplementation with high dose folic acid (4 mg) versus low dose (0.4 mg). We initiated this study five years ago under the sponsorship of the NIDCR, NICHD and the Gates Foundation. This proposal is to complete the current study by using the existing research infrastructure. We will continue involvement of the best participant sites, our pharmaceutical partner for inexpensive folate supplements and our experienced clinical trials partner, RTI, for data management. The primary aim is to assess the effect of folic acid supplementation of 4 mg/day on reducing the recurrence of CLP with power of 0.80 to see a 50% reduction under conservative assumptions. Secondary aims include comparing the effects of the two folic acid doses on health outcomes including serum and red cell folate levels; severity of CLP in offspring of trial mothers; rates of miscarriages and other birth defects; and effects on birthweight and gestational age.Under separate funding we will also examine the role of genes involved in folate metabolism on folate, B12 and homocysteine levels. This project addresses a fundamental challenge in the clinical care of families with one or more individuals with a cleft; that is, how to manage recurrence prevention. There are currently an estimated 1,000 births a year of children with clefts coming from high risk families in the US. If we were to realize a 50% reduction in CLP in these families, in the US alone, we would decrease the personal burden on each individual child and family and save $100 million in cleft-related economic costs per year.